Therapeutic a-1-microglobulin ameliorates kidney ischemia-reperfusion injury
Burmakin, Mikhail ; Gilmour, Peter S. ; Gram, Magnus LU
; Shushakova, Nelli
; Sandoval, Ruben M.
; Molitoris, Bruce A.
and Larsson, Tobias E.
(2024)
In American Journal of Physiology - Renal Physiology
327(1).
p.103-112
- Abstract
a-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection... (More)
a-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy. NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.
(Less)
- author
- Burmakin, Mikhail
; Gilmour, Peter S.
; Gram, Magnus
LU
; Shushakova, Nelli
; Sandoval, Ruben M.
; Molitoris, Bruce A.
and Larsson, Tobias E.
- organization
- publishing date
- 2024-07
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- A1M, IRI, kidney injury, proximal tubules
- in
- American Journal of Physiology - Renal Physiology
- volume
- 327
- issue
- 1
- pages
- 103 - 112
- publisher
- American Physiological Society
- external identifiers
-
- scopus:85196767348
- pmid:38779750
- ISSN
- 1931-857X
- DOI
- 10.1152/ajprenal.00067.2024
- language
- English
- LU publication?
- yes
- id
- a601467b-7061-4ef0-b2ee-3e24c803088b
- date added to LUP
- 2024-10-31 10:36:20
- date last changed
- 2025-07-11 09:20:46
@article{a601467b-7061-4ef0-b2ee-3e24c803088b,
abstract = {{<p>a-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy. NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.</p>}},
author = {{Burmakin, Mikhail and Gilmour, Peter S. and Gram, Magnus and Shushakova, Nelli and Sandoval, Ruben M. and Molitoris, Bruce A. and Larsson, Tobias E.}},
issn = {{1931-857X}},
keywords = {{A1M; IRI; kidney injury; proximal tubules}},
language = {{eng}},
number = {{1}},
pages = {{103--112}},
publisher = {{American Physiological Society}},
series = {{American Journal of Physiology - Renal Physiology}},
title = {{Therapeutic a-1-microglobulin ameliorates kidney ischemia-reperfusion injury}},
url = {{http://dx.doi.org/10.1152/ajprenal.00067.2024}},
doi = {{10.1152/ajprenal.00067.2024}},
volume = {{327}},
year = {{2024}},
}